Motor impairment following ischemic stroke remains a leading cause of disability and reduced quality of life for our veterans and the general population. Physical therapy (PT) has been the mainstay of rehabilitation to restore motor function, but there is a clear need to improve and expand rehabilitation strategies. The use of adjunct medication has been extensively studied as one approach to enhance clinical outcomes. At present there are no drugs indicated for the purpose of enhancing rehabilitation-aided motor recovery. The specific objective of this pilot study is to provide proof-of-concept evidence in a rat model of ischemic stroke that serotonergic drugs hold promise for further development as adjuncts to PT-aided motor recovery. Our specific hypothesis is that increasing synaptic serotonin will enhance neural plasticity and improve long term motor outcome following stroke when paired with physical therapy. In a recent clinical trial the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) fluoxetine enhanced PT-aided motor recovery following stroke. However, the longevity of this effect was not determined and motor improvement was associated with significant alleviation of depression. It has yet to be established that SSRI-induced motor improvement following stroke is a) associated with lasting neural plasticity or b) reflects anything more than an antidepressant action that increases volitional activity, which could be achieved by a number of different drugs. This is an important consideration as it is estimated that at most 40% of patients develop post-stroke depression which could potentially limit the utility of antidepressants in stroke rehabilitation. This pilot project will establish whether drugs that increase serotonergic activity can enhance motor improvement irrespective of antidepressant action. Aim I will study fluoxetine in order to compare our results with the literature. Aim II will study the serotonin-releasing drug fenfluramine, which induces greater increases in synaptic 5-HT than fluoxetine but has no antidepressant efficacy. The efficacy of each drug to induce motor improvement and neurite outgrowth, with or without PT, will be determined following short- term and extended treatment. In addition we will test whether treatment delay alters adjunct efficacy. In all treatment paradigms the assessment of motor activity will continue beyond duration of drug treatment to establish the lasting nature of improvement. We will follow our established methods for controlling the level of PT among groups. Neurite outgrowth from the contralesional sensorimotor cortex will be assessed by anterograde tracing. We expect to find that short term treatment with 5-HT-enhancing drugs paired with PT will provide greater improvement in motor function post-stroke than PT alone. Moreover, enhanced motor improvement will be associated with neuronal re-innervation of stroke-denervated motor regions (red nucleus and spinal cord) from the contralesional cortex. By controlling for level of PT, comparing 5-HT enhancers with or without antidepressant action, studying short-term and extended treatment, and establishing the long-term nature of improvement along with neurite outgrowth, the present proposal will yield novel and important data to establish the utility of 5-HT drugs as adjunct therapy in stroke. The findings of this pilot project will provide the framework for future studies identifying the specifc serotonergic mechanisms that can be used to optimize rehabilitation paradigms for improved functional recovery following stroke. PUBLIC HEALTH RELEVANCE: Stroke is the leading cause of motor impairment leading to long-term disability and reduced quality of life for our veterans and the general population. Of the estimated 700,000 Americans suffering a stroke each year 40% are left with moderate impairment and up to 30% have severe disabilities. Direct inpatient and outpatient annual costs to the Veterans Health Administration (VHA) are in excess of $300 million with cost of care correlating with level of disability. Physica therapy (PT) remains the primary strategy to improve motor function, but there is a clear need to enhance its efficacy. The goal of this pilot project is to provide proof of concept data that serotonin-modulating drugs hold promise for further development as adjuncts to PT-aided motor recovery following ischemic stroke. The findings of this pilot project will provide the framework on which to develop more efficacious drug-enhanced rehabilitative therapy for testing and translation to the clinic. Such therapy will improve the quality of life for our veterans at reduce cost to the VHA.